A convergence of histological, biochemical and genetic evidence links the widespread neuronal loss characteristic of Alzheimer's disease (AD) with deposits of β-amyloid that pervade the brains of AD patients. The principal component of extracellular β-amyloid is the β-amyloid protein (Aβ). The Aβ peptide is not directly expressed as a functional protein entity1 but is released by the processing of the much larger amyloid protein precursor (APP) protein2, 3. Aβ appears to be a normal product of cellular APP catabolism and is found as a soluble component of human cerebrospinal fluid (CSF) and plasma4-6. While Aβ can contain between 39 and 43 amino acids, the predominant species in brain are Aβ40 (40 residues) and Aβ42 (42 residues)7, 8. Analysis of material purified from human tissue suggest that up to 40% of the Aβ pool in AD brain consists of low molecular weight cross-linked β-amyloid protein species we have coined “CLAPS”9. Covalent cross-linking of Aβ appears to involve oxidation of the protein, which is tied to the peptide's propensity to bind the redox active metals copper and iron10. The mechanism of Aβ neurotoxicity remains controversial. However, evidence is mounting that the most neurotoxic forms of Aβ are not mature fibrils but prefibrillar oligomers or protofibrils11, which would include CLAPS. Notably, recent studies have demonstrated that the most toxic CLAPS maybe cross-linked dimeric species of Aβ12, 13. Despite the abundance and harmful bioactivity shown for CLAPS, the vast majority of currently available data has focused on non-oxidized monomeric forms of the peptide.
Interest in autoimmunity to Aβ has been stimulated by recent findings that amyloid burden in transgenic animal models can be attenuated by circulating anti-Aβ antibodies14-16. β-amyloid deposition can be inhibited by either peripheral infusion of exogenous anti-Aβ antibodies (passive immunization) or autoimmunity induced by immunization with synthetic Aβ peptide. Initial studies suggested anti-Aβ antibodies aid in the clearance of amyloid by crossing the blood brain barrier (BBB) and binding directly to plaques. However, subsequent studies have suggested that antibodies17 and other Aβ binding agents18 may not need to cross the BBB to be effective in inhibiting cerebral Aβ plaque formation. In this model, Aβ is bound and sequestered in the periphery and prevented from crossing back into the brain, thus promoting a net flux out of neurological tissue17.
Whatever the mechanism, the use of circulating anti-Aβ antibodies is a therapeutic strategy being actively pursued. Unfortunately, dosing in the first clinical trial using Aβ vaccination to treat AD patients was terminated in phase II because of complications associated with inflammation of the CNS vasculature19. None the less, limited data suggest that amyloid load may have been attenuated in some trial subjects by autoantibodies specific for insoluble Aβ deposited as Aβ-amyloid20. Despite the earlier problems, clinical trials aimed at elevating anti-Aβ antibody levels in AD patients will most likely proceed. Therefore, it is imperative to advance our understanding of the autoimmune response to Aβ and its derivatives with greater alacrity.
The presence of anti-Aβ immunoreactivity in human serum and CSF was first reported in 1991 by Mönning et al.21. Subsequently, Epstein-Barr virus (EBV) transformed B cells from AD patients have been shown to secrete anti-AD antibodies22. More recently, several studies have used ELISA assays to compare anti-Aβ autoimmunoreactivity in control and AD plasma and CSF. However, a consensus has yet to emerge as to whether anti-Aβ autoantibodies are elevated23, depressed24, 25 or unchanged26 in AD patients compared to non-demented controls. The future success of AD therapies based on anti-Aβ antibodies will require greater delineation of the naturally occurring autoantibodies to Aβ.
Although a pattern of decline in AD patients is generally clinically recognizable as the disease progresses, reliable diagnostic methods are lacking. The only definitive diagnostic test for AD at this time is to determine whether amyloid plaques and tangles are present in a subject's brain tissue, a determination that can only be done after death. Thus, due to the lack of suitable diagnostic methods, health-care professionals are only able to provide a tentative diagnosis of AD in an individual, particularly at the early to mid stages of the disease. Although these diagnoses can indicate that a person “likely” has AD, the absence of a definitive diagnosis reflects a critical need for more accurate and reliable AD diagnostic tests.
In addition to the absence of reliable diagnostic methods, the are also very limited treatment options available for patients suspected of having and/or diagnosed as having AD. Several drugs have been approved in the US for treatment of early and mid-stage AD, but they have significant detrimental side effects and limited efficacy. The lack of effective treatments for AD means that even with a diagnosis of probable AD, the therapeutic options are quite limited. Thus, there is a significant need for effective compounds and methods for preventing and/or treating AD.